title: Chronic exposure to valproic acid promotes insulin release, reduces KATP channel current and does not affect Ca (2+) signaling in mouse islets.
abstract: Hyperinsulinemia is one of the reported side effects of valproic acid (VPA), a medicine used to treat epilepsy. However, its underlying mechanism remains unknown. The present study was designed to investigate a direct effect of VPA on insulin secretion by using mouse pancreactic islets and β-cells. VPA had no acute effect on insulin secretion from islets, or on cytosolic Ca(2+) ([Ca(2+)]i) in single β-cells. However, following long-term exposure to VPA (48 h), both basal and glucose-stimulated insulin secretion were markedly elevated (5-fold), while the insulin gene expression level was unaltered. Following long-term exposure to VPA, β-cells showed a decrease in whole cell KATP channel current. However, the increase in [Ca(2+)]i in response to the sulfonylurea drug, tolbutamide was attenuated. The present study shows that VPA has no acute effects, but long-term treatment results in enhancement of both basal and glucose-stimulated insulin secretion. This long-term effect may mediate the KATP channel, while VPA can also attenuate the effect of the KATP channel blocker tolbutamide.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University, School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Manaka
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.forename: Rauza S
authors.initials: RS
authors.lastname: Rita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maejima
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D007328:Insulin; D054086:KATP Channels; D026902:Potassium Channel Blockers; D014635:Valproic Acid; D014044:Tolbutamide